Metastatic Colorectal Cancer: First-Line Therapy by Biomarker

Authored by Chinmay Jani, published on 2026-11-06 03:40:49.0

Newly Diagnosed Metastatic Colorectal Adenocarcinoma
- Confirm Unresectable Disease and Multidisciplinary Assessment
  
  Assess ECOG, treatment goals, CEA, MSI/MMR, expanded RAS, BRAF V600E, primary sidedness, and comprehensive molecular profiling. If treatment cannot wait, choose an appropriate interim strategy without assuming anti-EGFR eligibility, while completing molecular testing.
  - MSI-H/DMMR?
    - Pembrolizumab or Nivolumab + Ipilimumab
      
      First-Line Immunotherapy: Pembrolizumab or nivolumab + ipilimumab, if eligible.
    - BRAF V600E?
      - Encorafenib + Cetuximab + Fluorouracil-Based Chemotherapy
        
        BREAKWATER trial regimen based on February 2026 FDA approval of encorafenib + cetuximab + fluorouracil-based chemotherapy.
      - RAS Mutation?
        
        FOLFOX or FOLFIRI + Bevacizumab; Consider FOLFOXIRI + Bevacizumab in Selected Fit Patients
        
        For selected fit patients: FOLFOXIRI + bevacizumab.
        
        Left-Sided Primary?
        
        FOLFOX or FOLFIRI + Cetuximab or Panitumumab
        
        FOLFOX or FOLFIRI + Bevacizumab; Consider FOLFOXIRI + Bevacizumab in Selected Fit Patients
        
        For selected fit patients: FOLFOXIRI + bevacizumab.

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